Updates in the Management of Geographic Atrophy in Dry Age ...Pg.2 pdates in the Management of eographic Atrophy in Dry Age-Related Macular Degeneration CME Target Audience This activity

Updates in the Management of Geographic Atrophy in Dry Age-Related Macular Degeneration CME Supported by an independent educational grant from Genentech, a member of the Roche Group.

www.medscape.org/roundtable/geographic-atrophy

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Updates in the Management of Geographic Atrophy in Dry Age-Related Macular Degeneration CME

Target AudienceThis activity is intended for ophthalmologists, optometrists, and other healthcare professionals who treat patients with AMD.

GoalThe goal of this activity is to discuss the progression to geographic atrophy in patients with dry AMD, including assessment and management.

Learning ObjectivesUpon completion of this activity, participants will be able to:

1. Assess the development of geographic atrophy in dry age-related macular degeneration (AMD)

2. Evaluate current and emerging approaches for the assessment and treatment of geographic atrophy in dry AMD

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Medscape, LLC designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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CME Released: 12/14/2015; Valid for credit through 12/14/2016

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Faculty and DisclosuresAs an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines “relevant financial relationships” as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

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David M. Brown, MD Clinical Professor of Ophthalmology, Baylor College of Medicine; Director, Clinical Research, Retinal Consultants of Houston, Houston, Texas

Disclosure: David M. Brown, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Alcon Laboratories, Inc.; Allergan, Inc.; Alimera Sciences; Bayer HealthCare; Genentech Inc.; Novartis Pharmaceuticals Corporation; Optos; Regeneron Pharmaceuticals, Inc.; Roche; ThromboGenics, Inc.Received grants for clinical research from: Alcon Laboratories, Inc.; Allergan, Inc.; Allegro Ophthalmics, LLC; Bayer HealthCare; Clearside Biomedical, Inc.; Genentech Inc.; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; Roche; ThromboGenics, Inc.

Dr Brown does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Brown does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Carl D. Regillo, MD Professor of Ophthalmology, Thomas Jefferson University; Director, Retina Service, Wills Eye Hospital, Philadelphia, Pennsylvania

Disclosure: Carl D. Regillo, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Acucela Inc.; Alcon Laboratories, Inc.; Allergan, Inc.; Genentech, Inc.; Regeneron Pharmaceuticals, Inc. Received grants for clinical research from: Acucela Inc.; Alcon Laboratories, Inc.; Allergan, Inc.; Genentech, Inc.; Regeneron Pharmaceuticals, Inc. Dr Regillo does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Regillo does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


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Dante J. Pieramici, MD Assistant Clinical Professor of Ophthalmology, Doheny Eye Institute, Los Angeles, California; Co-Director, California Retina Research Foundation, Santa Barbara, California Disclosure: Dante J. Pieramici, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Genentech, Inc. Received grants for clinical research from: Genentech, Inc. Dr Pieramici does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Pieramici does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

EditorCharlotte WarrenScientific Director, Medscape, LLC

Disclosure: Charlotte Warren has disclosed no relevant financial relationships.

CME ReviewersRobert Morris, PharmDAssociate CME Clinical Director, Medscape, LLCDisclosure: Robert Morris, PharmD, has disclosed no relevant financial relationships.

Danica J. Marrelli, ODClinical Professor; Director, Ocular Diagnostic and Medical Eye Service, University Eye Institute, University of Houston College of Optometry, Houston, Texas

Disclosure: Danica J. Marrelli, OD, has disclosed the following relevant financial relationships:Served as an advisor or consultant for: Aerie Pharmaceuticals, Inc.; Alcon Laboratories Corp.; Allergan, Inc.; Carl Zeiss MeditecServed as a speaker or a member of a speakers bureau for: Alcon Laboratories Corp.

Peer ReviewerThis activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

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David M. Brown, MD: Hello, my name is Dr David Brown. I am a clinical professor of ophthalmology at Baylor College of Medicine and a director of clinical research at Retina Consultants of Houston in Texas. This program is titled “Updates in the Management of Geographic Atrophy in Dry Age-Related Macular Degeneration.”


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I would first like to introduce the faculty joining me today: Dr Carl Regillo, professor of ophthalmology at Thomas Jefferson University and director of the retina service at the Wills Eye Hospital in Philadelphia, Pennsylvania; and, from the West Coast, Dr Dante Pieramici, director of the California Research Foundation and partner in the California Retina Consultants in Santa Barbara. Welcome, gentlemen.

Carl D. Regillo, MD: Thanks, Dave.

Dante J. Pieramici, MD: Thanks, Dave.

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Dr Brown: First of all, I would like to mention that this program will include a discussion of, potentially off-label treatment options but the majority of the discussion will be on investigational agents that are part of US Food and Drug Administration (FDA) trials or soon-to-be FDA trials and not approved by the FDA for use in the United States.

The goal of the program is to discuss the progression of geographic atrophy in patients with dry age-related macular degeneration (AMD), including how we assess patients, what risk factors we look for, management now, and potential future novel agents for the management of geographic atrophy.


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Geographic atrophy, a form of AMD, is a process in which the retinal pigment epithelium disappears in the area underneath the photoreceptors. Everybody with AMD starts with drusen formation, which can progress to 1 of 2 forms of complex or severe macular degeneration: neovascularization or geographic atrophy. When I started practice the majority of people with AMD went blind from wet AMD or neovascular disease; only approximately 10% actually became legally blind from geographic atrophy.

Now that we have been successful in our anti-vascular endothelial growth factor (VEGF) treatment in neovascular AMD, there is actually a larger proportion of patients who are going blind from geographic atrophy either due to the process itself or in patients whose vision has been saved from neovascular complications and geographic atrophy progressed to take over their center vision. Currently there is no treatment for geographic atrophy. We are going to talk about a number of potential treatments, but first, let’s talk about definitions. Dr Regillo, how do you define geographic atrophy?

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Dr Regillo: I define it clinically as identifying areas of discrete retinal pigment epithelium (RPE ) loss during the course of a normal funduscopic examination.[1] What we see is the lack of RPE under the retina that is usually in the perifoveal area at first and then tends to expand. Often, there are associated features like soft drusen and RPE changes. But geographic atrophy by definition is zones of missing RPE that we can see clinically. Histopathologically, it is not just missing RPE because when the RPE has degenerated, you typically see underlying choriocapillaris atrophy, and there is overlying outer neurosensory damage or loss, too.

Dr Brown: Do you have anything to add to that, Dr Pieramici?

Dr Pieramici: Carl summed it up well. I would just emphasize that it really is a process. It is more than just loss of the RPE. Optical coherence tomography (OCT) and histopathology have shown us that we are losing the choriocapillaris layer. We are also losing the photoreceptor layer, and probably other layers inner to the retina are being affected in this process as well. So, it is really a more diffuse process than just the loss of pigmentation.

Dr Regillo: And because there is a permanent loss of neurosensory retina, those areas of discrete atrophy are permanently dead tissue. There is scotoma in those areas.

Dr Brown: It is simplistic, but I tell my patients that the RPE is one of the hardest working parts of the body and so it wears out first. Most patients lose vision from new blood vessels that grow a leak, but sometimes that layer wears out like carpet and there are threadbare patches. Patients seem to understand that analogy.


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Dr Regillo: We should talk about the term “late AMD.” Late AMD can be either center-involving geographic atrophy or the transformation to neovascular AMD. A lot of large drusen puts a patient at increased risk for either of those late forms of AMD.[1] Unfortunately, by just looking at a patient at one point in time, if there is no atrophy we cannot predict whether they are more likely to go the neovascular route or the geographic atrophy route. That is the problem. We have no way either phenotypically or genetically to determine whether or not they are going to go pure GA or whether they are going to go neovascular.

Dr Brown: Deposits under the retina above the RPE, the so-called pseudo-reticular drusen, may be another factor that increases the risk of geographic atrophy.[2] I see that most on the near infrared fluorescence on the Heidelberg image -- not the OCT but the near infrared fluorescence image in which they often really pop out and you can see those areas of pseudo-drusen or reticular drusen.

Dr Pieramici: That is a great point. It is a clinical characteristic that was identified many years ago and just now, particularly with OCT, we are able to figure out that these drusen are actually in front of the RPE. These drusen are associated with late stages of AMD, either neovascular or geographic.

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Dr Brown: Dr Regillo, can you tell us a little about the demographics of geographic atrophy? Which groups are getting geographic atrophy and what are the risk factors outside of genetics?

Dr Regillo: Age is the big factor, as prevalence goes up exponentially with age. A patient in the 65 to 74 years age range has a prevalence of geographic atrophy of less than 1%. It goes up to approximately 1% in patients in their early 70s/80s, then up to 4%; and really high, more than 20%, in our oldest patients (older than 90 years).[3] This is an age group that is expanding quite rapidly -- we routinely see patients older than 90 years of age. And now, 1 out of 5 have some degree of GA. That is big.

Family history is an independent risk factor for the development of advanced AMD, particularly GA, as is smoking. Smoking is a significant risk factor across the board for everything, particularly AMD.[4,5]

Finally, there are genetics. We do not routinely test patients in practice but there are known identifiable genetic polymorphisms that put patients at increased risk for more advanced AMD, including GA.[6]

Dr Brown: Dr Pieramici, can you address genetic markers? Do you routinely test for them? Also, please talk about the mechanisms that lead to geographic atrophy.


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Dr Pieramici: The physiology is not completely worked out, but it is clearly multi-factorial. There may be other factors in the environment that are stimulating the retina -- oxidation, hyperoxidation, peroxidation changes, and such -- that play a role. One thing we have learned, though, is that there may be an inflammatory component to this disease process. When we looked at the drusen, the precursor to geographic atrophy, that accumulate here we found that complement factor proteins were present, along with other inflammatory proteins.[7-11] There may also be a link with things like amyloid, which we see in patients with Alzheimer’s disease. There is no doubt that this complement, or inflammatory, factor is gaining some ground. The other line of evidence comes from genetics and the fact that we find a lot of associations with abnormalities in the complement pathway proteins genetically with AMD.[9]

Dr Brown: ARMS2 is also an independent non-confluent related genetic factor.[6] It may just be in the Northern European gene pool; we do not know. Do you find a use for genetic testing in your patients?

Dr Regillo: Not particularly, because at this time we just cannot act on that information. There are commercially available products which can easily look for the genetic profile that puts a patient at either increased or decreased risk. Some patients and family members want to know that. But, unfortunately, we just cannot act on it. We cannot change them. And it does not really affect how we manage patients. In other words, we still rely on the patient’s phenotype and clinical features to determine how closely we follow them.

Dr Pieramici: I think that is right. The phenotype pretty much dictates our evaluation of patients right now. Genetic testing does not add that much. We can look clinically at the patient and pretty much guess that if they have a lot of drusen and high-risk characteristics, they are probably going to have one of these genetic markers. There is a 50%, 60% chance they may be associated with ARMS2 or CFH so testing does not add a whole lot to the picture.[6] Now, we may find a biomarker that is useful for identifying certain types of patients who may respond to treatment better.

Dr Brown: Certainly, family history is one factor but the most pertinent thing is the patient’s other eye. The other eye has the same genetic profile and is the same age, so if it has geographic progression, there is certainly a high-risk of that happening.

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Now we are going to talk about how we functionally assess patients with geographic atrophy, or severe dry AMD. My patients come in with complaints about vision that can be hard to assess: “Doc, I have trouble driving at night,” or “I have trouble going from light to dark.” What do you think are the best functional assessments? And how do you assess patients from a functional standpoint?

Dr Regillo: In practice, all we do in the office objectively is measure Snellen visual acuity and distance acuity. That gives us some information but unfortunately not the whole story. A patient can have a lot of atrophy and so have a lot of difficulties with certain visual task, like reading for example, but if the atrophy does not affect the foveal center, their acuity may be measured as good. Their acuity will be most severely affected when the atrophy progresses to involve the foveal center.

I should note that there are a lot of different ways to measure vision function. But they are not done routinely in practice and we do not have them available in our offices.

Dr Brown: There’s microperimetry, reading speed -- basically all the experimental testing to try to prove whether a drug works.

Dr Pieramici: Correct. It is cumbersome to do these tests in our practice. Clearly though, they do have a role. I think we do a poor job of assessing how well these patients are functioning. They continue to come in with 20/40 vision but complain that their vision is getting worse. Tests like low luminance, visual acuity, reading speed assessments, or microperimetry get more to the essence of why they are probably having problems. Those tests show that patients are missing areas in their vision. So I think they could be helpful, but we have to make them practical to use in our clinics.

Dr Regillo: They are important diagnostic tools from a clinical study standpoint. For example, they can measure end points to see whether a given intervention is going to slow the progression of not only the loss of visual acuity but of other ways geographic atrophy affects a patient’s visual function, such as reading speed, low luminance, and visual acuity. So, they are important tests, but they are usually used at academic centers or in clinical studies. Right now, we can assess symptoms related to atrophy best through just listening to what the patient describes.

Dr Pieramici: It is the result of having poor functional tests that the end points of most of our trials are anatomical, not visual end points, as we traditionally do in clinical trials in ophthalmology.


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Dr Brown: Let’s talk about the clinical examination. Although you can see a lot of geographic atrophy by looking at a patient’s eye, there is a lot you cannot see. For example, if there is overlying neovascularization, you often miss geographic atrophy. On OCT, if you get that shadowing through the window defect of RPE atrophy, it is a definite signal of geographic atrophy and that is how it is often measured in clinical trials.

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Fundus autofluorescence is also helpful in my practice in terms of figuring out how big the area is and whether it is increasing. Frank Holz has shown that there are some phenotypes with increased autofluorescence at the edge.[12] In my mind that is because the RPE cannot do its job so lipofuscin may be building up. Is there anything in particular you use, and do you find that fluorescein is helpful?

Dr Regillo: I agree with you that autofluorescence images are a nice way to quantify the extent of the atrophy and to look over time to see how and at what rate it is growing, which varies from patient to patient. How it grows varies. It does not always go into the foveal center; sometimes it wraps around it. It is highly variable and we cannot predict how it will grow. So, it is a nice way to show patients and to tell us how much progression there is, where it is occurring, and so forth. So I also like fundus autofluorescence.


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Fundus photography can be good, especially if there is some good contrast. With a darker, pigmented fundus, you can see atrophy better than when it is a lighter pigmented fundus, and that is where autofluorescence comes in. A fluorescein angiogram can show you geographic atrophy very nicely, but I hate to put a patient through regular fluorescein angiograms. There is an invasive aspect to it although it is still relatively safe.

Dr Pieramici: I agree. I think multimodal imaging is key in these patients because no one measurement is ideal. We find with autofluorescence we can really see the boundaries pretty well. With OCT, we can see what is going on in the retina. We can actually see whether there is some disease that lies outside the boundaries we find with autofluorescence. Color photography can be a little tricky but it is useful to document other features associated with the AMD. I do not really find much use for angiography either. OCT angiography may have a role. We will have to wait and see.

Dr Regillo: I like angiography in the setting of a patient with dry AMD with some atrophy and a lot of other features like drusen. So an angiogram is sometimes a good way to look for or rule out choroidal vascularization as a source for the progression of visual symptoms.

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Dr Brown: The autofluorescence and/or near-infrared fluorescence you see on the OCT is often a good way to show family members that the patient is missing parts of their vision. They always ask: “Is it safe for Grandma to drive?” And Grandma’s center visual acuity may be fine but a lot of people only have preservation of a small area, and are missing large areas. As an educational tool it can be helpful as well.

We are going to move on to potential interventions, including what we can do now for patients with geographic atrophy, and then take a look at some of the novel treatments that are currently in clinical trials.


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First, Dr Pieramici, can you give us a summary of the role of supplements in geographic atrophy and what you tell your patients?

Dr Pieramici: There is a role for supplements in patients with AMD.[13] When patients have at least intermediate AMD based on clinical examination, supplements can help reduce progression to advanced AMD. If, however, a patient has geographic atrophy or is at risk for geographic atrophy, supplements do not appear to reduce the risk of progression or the incidence rate. In other words, most of the benefit of supplements is that they reduce the incidence of neovascular AMD. So, if I have a patient with AMD I am going to try to reduce wet AMD. But if they specifically say, “I’m starting to develop some atrophy, should I be taking more vitamins?” I would tell them there is no good evidence to support the use of vitamins for atrophy or the progression of atrophy.

Dr Brown: Dr Regillo, what do you say when your patients develop large central geographic atrophy with decreased visual acuity, and they ask whether they need to keep taking their vitamins?

Dr Regillo: As Dante mentioned, the original AREDS or modified AREDS2 formula is what we would recommend in a patient with dry AMD when there is are at least some intermediate or large drusen.[13] The reason is to decrease the risk of so-called late AMD, which is, for the most part, neovascular AMD. So, yes, I tell patients to continue on supplements regardless of the presence or absence of atrophy. There are also other things we can do, though we do not have proof that they work.

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Certainly if a patient is a smoker, it is a good idea for them to stop. Smoking is bad for the eyes, bad for this condition. So, there is much more to the conversation than telling patients to take their AREDs vitamins. There are other lifestyle modifications that theoretically might be beneficial, including having a good diet. I like to talk about the colorful plate. The average American plate is full of tan and brown food; it is not colorful. Having color means food that is red, green, orange – that contain nutrients that might have anti-oxidant effects and other potential benefits. Again, there is no evidence that these types of recommendations decrease the risk of patients going on to more atrophy or the rate of atrophy progression but, nonetheless, they make sense and a good diet is worth recommending even if we cannot prove whether or not it is useful.


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Dr Brown: We are now going to go on to some of the most exciting stuff: the clinical trials and new avenues for treatment. We are going to start with several of the novel therapies. The first one from the recent era looked at neuroprotection and the ciliary neurotrophic factor (CNTF) implant.[14] Dr Pieramici, can you briefly talk about that and what the results were?

Dr Pieramici: Geographic atrophy is a neurodegenerative disease, so it makes sense that you would want to try to protect the nerve cells, make them healthier and not go into apoptosis or death. CNTF is one such approach that was thought might be helpful. Since they would have to deliver factor over a long period of time, an interesting implantable device was developed where there are actually cells in the device making this like a neurotropic factory.[14] I thought it was a fascinating delivery system but we do not know whether or not it is actually going to have a benefit. Another approach is the agent brimonidine, which we have used for glaucoma treatment in the past, which may have neuroprotective factors as well. There are ongoing studies looking at agents like this and injecting them into the eye -- not just a drop but an actual injection into the eye, to try to protect these cells, to keep them healthier for a longer period of time.

Dr Brown: So the initial data from the CNTF trial showed an increase in cellular thickness but not necessarily functional gains. I think they are still evaluating this but currently there are no plans for immediate trials.

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The next thing we are going to talk about is cell cycle modulation, which is a little tough to wrap your head around it. Essentially the thought is that if you have metabolically active cells and you can slow them down a little bit, you may be able to decrease the progression of an aging change. It is a similar idea to taking a beta blocker for the prevention of heart failure. Dr Regillo, can you fill us in on cell cycle modulation and that avenue going forward?

Dr Regillo: As you said, the thought is that with a visual cycle that has been up regulated, there are excessive toxic metabolite byproducts that are deposited, such as A2E. The idea is then to slow the cycle with an RPE65 inhibitor. There is a drug in phase 2/3 clinical trials called emixustat that is orally administered once a day. It slows the visual cycle, theoretically decreasing the amount of deposition A2E, this presumably toxic metabolic byproduct.[15] It is in clinical trials now and what we can hope for is the potential for slowing atrophy. We are not going to reverse atrophy, we are not going to halt it by slowing the visual cycle -- and that goes for most of the things that are being investigated now. It is hoped that they will slow the atrophy and decrease the risk of vision loss or the visual dysfunction associated with that progression.

Dr Brown: That trial is fully recruited. I guess we are expecting a preliminary result about a year from now?

Dr Regillo: Most of the clinical trials in dry AMD have end points of either 1 year, 18 months, or 2 years, which is enough time to show a difference between the control group and the active intervention arm.

Dr Brown: Just to briefly emphasize the difficulties of these trials: dry AMD and geographic atrophy are variable and often take a long time to progress. In phase 2 trials, you are trying to figure out whether an agent is safe. You would like to see a signal of efficacy, but you may not have the numbers to prove it.

Dr Regillo: That is an excellent point. In phase 2 testing for wet AMD, you can often get a good sense of whether something is working, but in phase 2 testing in dry AMD, there may be some hints of efficacy but certainly nothing definitive at that level.


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Dr Brown: Dante, let’s turn to anti-amyloid approaches. This has been talked about for Alzheimer’s disease, and there are a couple of different trials, one of which was stopped and one that is ongoing.

Dr Pieramici: As we previously discussed, we see the inflammatory components such as complement factor in drusen, but we also find amyloid.[16,17] There are a lot of similarities between AMD and Alzheimer’s disease, which has plaques that build up in the brain. In AMD, little plaques build up under the retina -- drusen --- and part of the constituents of these plaques is amyloid from beta amyloid. So trying to inhibit the buildup or get rid of these plaques is a rational treatment option.

Dr Regillo: It is also important to point out that we do not know cause and effect here. We do not know if the deposition of amyloid along the edges of atrophy and in drusen we see is an epi-phenomena, or whether it is actually driving the process. It makes sense that it is driving the process because it is toxic. Excessive amyloid deposition is toxic to cells.

Dr Brown: We saved probably the most exciting developments for last: Complement inhibition, in which we now have a phase 3 trial, and stem cell, which is on the front page of the newspapers and our patients always ask about.

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Carl, would you summarize your thoughts on the mechanism of and trials in complement inhibition.

Dr Regillo: There are a lot of players because this area looks promising, based on some positive phase 2 study results with lampalizumab, which inhibits complement factor D.[18] There are many different complement components that you can inhibit.[7-11] You can look downstream at common components like C3 or C5, or you can be more selective and target, for example, just the alternative pathway. The genetics seem to suggest that the alternative pathway is what is upregulated and perhaps is the culprit. That is based on the polymorphisms for complement factor H. So that is where inhibiting factor D comes in because that will, in essence, slow down or inhibit only the alternative complement pathway. It comes down to if you are going to target complement, are you going to do it globally and target C3, C5, or the membrane attack complex? Or, are you going to be specific? There are pros and cons to both approaches.

You can be specific and get the effect you want presumably without theoretical side effects like increasing the risk of infection in the eye. Complement has a good side -- the surveillance of foreign matter and microbes -- so it is possible that if you completely inhibit the entire complement system within the eye you might put the eye at increased risk for infection. So, it is a balancing act. Do we go for the alternative complement pathway or do we just knock out complement altogether in the eye?


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Dr Brown: First, let’s talk about the one completed trial in the C5 blocker.[19] What happened there?

Dr Regillo: The agent was eculizumab, an antibody that blocks C5. It was a short, 6-month study, with eculizumab administered intravenously. The study did not show any benefit in terms of slowing the progression of atrophy. We do not know if that means C5 inhibition does not work or that it was ineffective C5 inhibition -- meaning that the investigators did not get enough drug in the right place for a long enough timeframe. The drugs that we use to treat wet AMD are administered intravitreally, which is the best way to get the highest dose right where you want it. Everything else being tested -- all the other C3, C5, or factor D inhibition -- is using intravitreal administration.

Dr Pieramici: Yes, there are a number of challenges here. As you mentioned, there are a number of targets -- and it may be that it is not necessarily the wrong target but it may be the way the medication was delivered. It may not have gotten to the level that was necessary. It is tough to know. There may be a lot of hit and miss but it may be a miss not because of the agent but because of the way we targeted it.

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Dr Brown: Dante, you were one of the first presenters and an investigator in that phase 2 anti-factor D trial.[18] Why don’t you tell us the results of the phase 2 trial?

Dr Pieramici: Complement factor D (CFD) was selected to be an inhibitory agent with a monoclonal antibody for a number of reasons. First, the alternative pathway seems to be important. Second, factor D seems to be the rate-limiting step in the alternative complement pathway, so it seemed like a good target. The monoclonal antibody to inhibit this factor is called lampalizumab. Preclinical work seemed good. The phase 1 and 2 trials did not show any toxicity with this agent. It is an intravitreal agent that probably needs to be delivered every month, maybe every 6 weeks. We do not know. The phase 2 trial was called the MAHALO trial and in that trial they looked at delivering the drug monthly or every other month vs placebo or sham injection.[18] Patients who received the drug monthly had a reduced progression of geographic atrophy. This difference was seen early on -- there was a difference in the growth rates of these lesions overall within 6 months. There was no benefit in the every 2 or every other month injection arms, so there is clearly a dose response suggesting that monthly injections were necessary.

The other interesting thing that came out of this trial involved biomarkers. Could patients be selected who would be particularly susceptible to a potential benefit, meaning they might have a higher growth rate? A number of factors associated with geographic atrophy were looked at. The one biomarker that seemed to be associated with faster growth rates and a potential response was complement factor I (CFI), which is an inhibitory factor like complement factor H (CFH). If you have an abnormality in CFI you are unable to shut down the alternative complement pathway. There was a particular benefit in the subgroup of patients who were biomarker positive for CFI, with a 44% reduction in the growth rate of the lesion at 1 year -- almost a 50% reduction in the growth rate.


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Dr Brown: Based on the results of the MAHALO study, the lampalizumab trials are going forward into phase 3. This is a 1-year trial that it is thought will be extended and is enrolling now. Patients have geographic atrophy in both eyes; they cannot have had prior wet AMD, which eliminates a lot of patients.

There are also other complement drug trials that are currently enrolling patients: an anti-C3 agent, and an APL2 trial that is allowing patients with wet AMD in the fellow eye. So, there is a separate niche of patients going into that trial.

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As we wrap up, we will talk about what I must get a question a day on, from newspapers all over the world: “Did you hear about stem cells and do they cure blindness?” Dr Pieramici, what do you tell your patients?

Dr Pieramici: To my mind, things are preliminary. There are places in the world you can go to get all kinds of stem cells injected into anywhere in your body, and most of them are hemopoietic stem cells that they remove. But there is some interesting work being done looking at using RPE-type cells, neural cells as well. We all hope this will work one day. Whether it will work because the cells actually reintegrate into the anatomy or are going to release growth factors that potentiate or are neuroprotective in their function, we really do not know. It is too early to really reach any dramatic conclusions.

Dr Brown: Your thoughts, Dr Regillo?

Dr Regillo: Farthest along right now is stem cell-derived RPE cells.[20] They are entering phase 2 testing based on some preliminary good safety data and a hint of something positive happening visually in patients with advanced dry AMD. They are surgically implanting cell derived RPE cells under the retina stem. Now, this is in suspension. It is an injection of a suspension containing these cells. These are differentiator RPE cells. They are not injecting “pluripotential stem cells” and hoping that they grow into whatever is dead or dying. It is analogous to spraying grass seed under the retina and hoping that it grows grass. And yet, as Dante mentioned, we do not know whether the tissue can support the growth or what the long-term viability of these cells is.

But there are 2 basic approaches right now entering phase 2 testing. I think these studies will give us a good feel for whether or not this treatment path is going to be useful at all. One approach is to inject suspensions of RPE cells and the other is to grow a sheet of RPE cells on a sort of biomembrane and insert that into the eye. Again, I am using the analogy of grass seed vs sod grass to be placed in the area -- in and around the area of atrophy with the hope that that supports the other tissue that is present, either to reverse or to prevent further degeneration.

Dr Brown: It is an exciting time, and I do think if stem cells are going to work the eye is probably one of the first places this will be successful because this is a relatively immunoprotected area to begin with, which takes away one of the main problems of putting stem cells in a place where they are going to be rejected.


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I would like to thank the faculty, Dr Regillo and Dr Pieramici, for joining us today. We have had a good summary of the state of the art of geographic atrophy. Thanks to all of you for participating in this activity. Please click on the earn CME Credit link to revisit the questions presented at the beginning of the activity and see what you’ve learned. The CME posttest and evaluation will follow.

This transcript has been edited for style and clarity.

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AbbreviationsA2E = a lipofuscin fluorophore in human retinal pigmented epithelial cells in culture AMD = age-related macular degeneration APL2 = sodium/solute symporter family protein ARC1905 = anti-C5 aptamer AREDS = vitamin supplement containing vitamin C, vitamin E, zinc, copper, lutein and zeaxanthin AREDS2 = Age-Related Eye Disease Study (National Eye Institute) ARMS2 = age-related maculopathy susceptibility 2 ARVO = Association for Research in Vision and Ophthalmology BCVA = best corrected visual acuity C1/2/3/ etc = complement component 1,2,3/etc CFB = complement factor B CFH = complement factor H CFI = complement factor I CNTF = ciliary neurotrophic factor FDA = US Food and Drug Administration FHR1-3 = complement factor-related 1-3 GA = geographic atrophy HCL = hydrochloride MAHALO = Lampalizumab (anti-factor D) in patients with geography atrophy trials MASP1/2 = mannan-binding lectin serine peptidase 1/2 NEI = National Eye Institute OCT = optical coherence tomography RPE = retinal pigment epithelium RPE65 = retinal pigment epithelium-specific protein 65kDa SNP = single-nucleotide polymorphism VEGF = vascular endothelial growth factor References 1. Age-Related Eye Disease Study Research Group. The Age-Related Eye Disease Study Severity Scale for Age-Related Macular Degeneration: AREDS Report No. 17. Arch Ophthalmol. 2005;123:1484-1498. 2. Spaide RF, Curcio CA. Drusen. Characterization with multimodal imaging. Retina. 2010;30:1441-1454. 3. Buch H, Vinding T, Nielsen NV et al. 14-year incidence progression and visual morbidity of age-related maculopaty: The Copenhagen City Eye Study. Ophthalmology. 2005;112:787-798. 4. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology.1992;99:933-943. 5. Vingerling JR, Dielmans I, Hofman A, et al. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology.1995;102:205-210. 6. Caire J, Recalde S, Velazquez-Villoria A, et al. Growth of Geographic Atrophy on Fundus Autofluorescence and Polymorphisms of CFH, CFB,C3, FHR1-3, and ARMS2 in Age-Related Macular Degeneration. JAMA Ophthalmol. 2014;132:528-534. 7. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005 Apr 15;308:419-421.8. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005 Apr 15;308:421-424.9. Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007;357:553-561. 10. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005 April 15; 308:385-389.11. Gold B, Merriam JE, Zernant J, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006;38:458-462. 12. Mauschitz MM, Fonseca S, Chang P, et al. Topography of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2012;53:4932-4939. 13. Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol. 2001; 119:1417-1436. 14. Kauper K, McGovern C, Sherman S, et al. Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases. IOVS. 2012;53:7484-7491.15. Dugel PU, Novack RL, Csaky KG, Richmond PP, Birch DG, Kubota R. A Phase 2 Double-masked, Placebo-controlled, Dose Ranging Study of Emixustat Hydrochloride (ACU- 4429) in Subjects with GA Associated with Dry AMD. Presented at ARVO 2013. Abstract 4506.


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16. Johnson LV, Leitner WP, Rivest AJ, Staples MK, Radeke MJ, Anderson DH. The Alzheimer’s Aß-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. PNAS. 2002;99:11830–11835.17. Anderson DH, Talaga KC, Rivest AJ, et al. Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age- related macular degeneration. Exp Eye Res. 2004;78:243-256. 18. Regillo CD. Lampalizumab (anti-factor D) in patients with geography atrophy: the MAHALO phase 2 results. Paper presented at: the 2013 Annual Meeting of the American Academy of Ophthalmology; November 16-19, 2013; New Orleans, LA.19. Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al. Systemic complement inhibition with eculizumab for geographic atrophy in age- related macular degeneration: the COMPLETE study. Ophthalmology. 2014;121:693-701. 20. Schwartz SD, Hubschman J-P, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet. 2012;379:713-720.

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